# Factors Controlling Metabolic Flux in the Liver

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $488,379

## Abstract

Project Summary:
It is widely accepted that mitochondrial metabolism contributes to the development and progression of non-
alcoholic fatty liver disease (NAFLD), but the mechanisms of this process are poorly understood.
Hepatocellular mitochondria are unique in their ability and requirement to support biosynthetic, catabolic,
and substrate trafficking pathways. These functions are mediated by anaplerosis, non-oxidative pathways of
the TCA cycle that allow its intermediates to produce and recycle substrates. The downstream pathways
that require anaplerosis (e.g., gluconeogenesis and urea cycle function) are energetically costly. They are
also notably dysregulated by obesity and insulin resistance, but it is unknown how mitochondrial anaplerotic
function impinges on the progress of liver disease. It is suspected that changes in anaplerotic pathways of
liver mitochondria alter apparent mitochondrial function, redox state, and antioxidant capacity. This project
tests the hypothesis that the equilibrium between anaplerosis and downstream pathways impinge on
antioxidant capacity by modulating redox-mediated reactions in liver. Hence, seemingly unrelated
intermediary metabolism may have secondary effects on mitochondrial function and contribute to factors
like oxidative stress and inflammation in NAFLD. To test the hypothesis, we will use state-of-the-art stable
isotope tracer methods, NMR and MS to evaluate metabolic flux, and conditional knockout mice to establish
mechanism. Emphasis is placed on identifying how TCA cycle intermediates modulate antioxidant function
and the role of metabolic compartmentation. In the process, we will develop new tools and concepts that
can be tested and applied against human disease.

## Key facts

- **NIH application ID:** 10770550
- **Project number:** 5R01DK078184-15
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Shawn C Burgess
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $488,379
- **Award type:** 5
- **Project period:** 2008-02-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770550

## Citation

> US National Institutes of Health, RePORTER application 10770550, Factors Controlling Metabolic Flux in the Liver (5R01DK078184-15). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10770550. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*